Despite significant progress in drug discovery there is still a lack of effective therapies for a number of cancers, inflammation-linked diseases, viral diseases, or allergies. The immune response is a common factor for all these pathologies (Wickelgren, 2006, Science, 312: 184-187) and, therefore, provides a target for new drug discovery. Stimulation of immunity is also beneficial in promoting better responses to vaccines (adjuvants) and to control lipid and carbohydrate metabolism. Compositions that stimulate and modulate immune responses have a promise as medicines and adjuvants for use against a number of diseases.
Research in the past decade led to the discovery of Toll-like receptors (TLR) which were shown to play a major role in immune response to microbial infections (Medzhitov et al., 1997, Nature, 388: 394-397, Janeway & Medzhitov, 2002, Annu. Rev. Immunol. 20: 197-216, Bendelac & Medzhitov, 2002, J. Exp. Med, 195: F19-F23). The function of TLR receptors was demonstrated to the modulation of innate immunity (i.e., non-adaptive immunity) which acts as a system of defense for organisms against pathogens by launching of an inflammatory response. These receptors are activated upon recognition of pathogen-associated molecular patterns (PAMPs) (Carmalho et al., 2003, J. Exp. Med. 4: 403-411, Xu et al., 2005, Cell Immunol, 233, 85-89).
Physiological molecular mechanisms of induction of immune responses have been partially described for the currently known thirteen TLRs (Krishnan, et al., Exp Mol Med, 38:421-438, 2007; Roach, et al, PNAS, USA 102:9577-9582, 2005; Janeway & Medzhitov, 2002, Annu. Rev. Immunol. 20: 197-216, Heil et al., 2004, Science, 303: 1526-1529, Nishiya & DeFranco, 2004, J. Biol. Chem. 279: 19008-19017). TLR-4 and TLR-2 were shown to interact with CD14 and lead to dendritic cell (DC) maturation (Ismaili et al., 2002, J. Immunol., 168: 926-932) and NF-κB activation through mechanisms triggered by calcium signaling (Lilienbaum and Israel, 2003, Mol. Cell. Biol. 23: 2680-2698, Mogensen, et al., 2003, J. Immunol. 170: 6224-6233).
Among TLR-2 and TLR-4 agonists, the most studied are natural lipopolysaccharides (LPS) from cell walls of Gram-negative bacteria. Other known TLR-4 agonists include lipoteichoic acids of Gram-positive bacteria, Protein F of respiratory syncytial virus, Taxol from plants, HSP60 from bacteria, EDA in fibronectin and hyaluronan produced by hosts (Pasterkamp, et al., 2004, Eur J Clin Invest, 34: 328-334). Lately, with the development of synthetic monophosphoryl lipid A (MPL), a TLR-4 agonist (Stover, et al., 2003, J. Biol. Chem, 279: 4440-4449), a number of studies appeared on the utility of the synthetic compound for treatment and prevention of infectious diseases (Baldridge, et al., 2005, U.S. Pat. No. 6,911,434; Isogawa, et al., 2005, J. Virol., 79: 7269-7272) and allergic airway inflammation (Patel, et al., 2005, J. Immunol. 174:7558-7563).
Phosphorylated polyprenols have been offered as an agent for upregulating Th1-mediated immunity in living organisms and this application has been patented (Danilov, et al., 2003, U.S. Pat. No. 6,525,035). Cox and coworkers also reported criticality of C15 farnesyl isoprenoid group for cell signaling in the Ras pathway through farnesylation of signal proteins (Cox and Der, 1997, Biochim Biophys Acta, 1333: F51-F71). Polyisoprenyl phosphates were shown to play an important role in intracellular signaling through inhibiting of superoxide anion production in neutrophils (Levy, et al., 1997, Science, 389: 985-990). Morita, et al., (1999, Microbes Infect, 1: 175-186) showed that short, C5-C20 prenyl pyrophosphates may serve as antigens, the recognition of which is conserved in vertebrate evolution of γδ T cells. They later offered a potential model of prenyl antigen interaction with T-cell receptors (TCR, Morita, et al., 2001, J. Immunol, 167: 36-41). Those suggestions are in-line with earlier findings that the compounds of our prior patent protect organisms from viral infections (Danilov, et al., 2003, U.S. Pat. No. 6,525,035), that derivatives of shorter polyprenols may have direct antimicrobial effects (Fairlamb, et al., 2003) and that phosphorylated polyprenyls lacked ability to induce cytokines on their own and needed a co-inducers such as viruses, etc (Pronin, et al., 2000). However, despite results pointing to the potential significance of those compounds in cell signaling, cellular targets for 1,4-cis-polyprenyl phosphoryl derivatives have not been identified.
Naturally occurring glycosylated polyisoprenols isolated (purified components of defined structures) from the cell wall of Mycobacterium tuberculosis were shown to be presented by the CD1c protein and recognized by the T-cell antigen receptors (TCRs) (Moody, et al., 2000, Nature, 404: 884-888; Moody, 2001, Cell. Mol. Life Sci., 58:1461-1474). Later, using total extracts, it was shown that M. tuberculosis CD1 antigen presentation is regulated through TLR-2 which responds to known TLR-2 agonists produced by bacterial pathogens and used as total or partially purified lipid extracts (Roura-Mir, et al., 2005, J. Immunol. 175: 1758-1766). Since the effector molecules were not identified in this work, it is not known if the same components isolated in the work by Moody, et al., were the same effector molecules in the work by Roura-Mir, et al.
What is needed are compositions and methods for the modulation of immune responses mediated by TLRs and which are useful for conducting scientific research into TLR-mediated immune system functions, selecting for inhibitors and activators of TLR-mediated immunity and for the prevention and/or treatment of diseases and illnesses.